Cerebral malaria is a deadly complication of Plasmodium falciparum infection that is associated with the massive accumulation of infected erythrocytes in cerebral microvasculature. Parasite binding is mediated by the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. Recently, we discovered that parasites expressing DC8 and DC13 PfEMP1 are associated with cerebral malaria and showed that they bind to endothelial protein C receptor (EPCR) via the cysteine-rich interdomain region (CIDR) domain in PfEMP1. The finding that DC8 and DC13 PfEMP1 bind EPCR has important implications for cerebral malaria pathogenesis. EPCR is a receptor for activated protein C and plays a key role in regulating coagulation and endothelial barrier properties. These findings suggest there may be causal links between parasite cytoadhesion and microvascular pathology, such as a blockade of the protein C-EPCR interaction by DC8 or DC13-expressing infected erythrocytes. While this mechanism provides an appealing explanation for many of the pathophysiological correlates of cerebral malaria, a number of critical questions remain unanswered including to what extent DC8 and DC13 PfEMP1 inhibit EPCR function and identifying the combination of host receptors mediating cerebral binding. In this project, we will: 1. Determine if EPCR-binding parasites inhibit the protein C-EPCR interaction, 2. Determine if EPCR-binding parasites affect the cytoprotective and pro-barrier function of EPCR on endothelial cells and 3. Determine the combination of host receptors that act in concert with EPCR to mediate high affinity binding of DC8 variants to brain endothelial cells. This project will characterize the molecular mechanisms by which P. falciparum-infected erythrocytes adhere to brain endothelial cells, shed light on the pathogenic mechanisms associated with cerebral malaria, and may suggest anti-adhesive strategies or new treatment options to improve cerebral malaria outcomes.